This proposal deals with biology of adipocyte/macrophage fatty acid binding proteins (FABPs) as a model experimental system as they relate to the molecular mechanisms of obesity. FABPs are a family of cytoplasmic proteins expressed in a variety of cell types and bind to fatty acids, xenobiotics and retinoic acid. White adipocytes and macrophages co-express two FABP isoforms, aP2 and mal1, which have critical functions in both metabolic and inflammatory responses. Mice lacking aP2 have reduced insulin resistance associated with obesity, improved lipid metabolism and dramatically protected from atherosclerosis. The latter is predominantly related to the action of aP2 in macrophages. Mal1-deficient animals also exhibit moderately increased insulin sensitivity and altered lipid metabolism. Recently, we developed a mouse model lacking both aP2 and mall (aP2-mal1-/-) to determine the impact of these FABPs on systemic metabolic control. Interestingly, and unlike the individual FABP mutants, the aP2- mal1-/- mice are resistant to weight gain and increased adiposity and maintained their lean body mass on a high fat diet with no reduction in food intake but a significant increase in muscle AMP-activated kinase (AMP-K) activity. In the ob/ob model, the reduced adiposity phenotype and the increase in AMP-K activity are lost. However, in preliminary studies, aP2-mal1-deficient mice were dramatically protected against insulin resistance and fatty liver disease associated with either dietary or genetic obesity. We propose to study the impact of aP2-mal1-combined deficiency in detail with respect to adipogenesis and obesity using dietary and genetic (leptin-deficient) models. We will address the target cell types involved in this action of FABPs and address the potential involvement of macrophages. We will also address the role of AMP-kinase activation in muscle as a mechanism of increased fatty acid utilization, energy expenditure and weight reduction and test the sensitivity of peripheral organs to adipocyte-derived hormones leptin and adiponectin in the presence and absence of FABPs. We will develop additional experimental systems to generate insights into the mechanisms of action of aP2 and mal1, identify protein interactions with these FABPs in their target cells and study the pathways underlying their biology with respect to obesity. The adipocyte/macrophage fatty acid binding proteins play a central role in obesity and the associated disorders in mice and provide an outstanding tool to study the underlying mechanisms to many key components of the metabolic syndrome. The proposed studies will provide important insights regarding the mechanisms by which FABPs integrate inflammatory and metabolic pathways regulate systemic energy homeostasis.